Project Summary How animals regulate growth, development and behaviors in response to changes in nutrient availability and metabolic status is a fundamental biological problem that is closely related to human diseases and health. While major advances have been made over the last decade in understanding TOR, insulin receptor and other signaling systems that sense the levels of sugar and amino acids to control various cellular and physiological functions, the study of the mechanisms by which cells and animals respond to changes in nucleotide levels to regulate development and other physiological functions is lacking, even though nucleotide levels have been shown to impact several cellular processes including cancer progression and certain human disorders. The goal of this proposal is to discover and analyze the mechanism of such a nucleotide-responsive regulatory system. By using genes involved in nucleotide metabolism in both sthe worm and its food source E. coli, we have established a unique model system where we observe a profound impact of uridine and thymidine (referred to as U/T) on germline development. Results from our preliminary study, including a suppressor screen, have indicated two key factors in the U/T sensing system leading to the hypothesis that an unknown system involving a ribonuclease acts upstream of a Notch signaling pathway to regulate germline proliferation and pyrimidine metabolic pathways. We will test this hypothesis by studies under three specific aims: (1) determine how Notch receptor (glp-1) expression is regulated by U/T levels, including the identification of the U/T-responsive element and potential upstream regulator; (2) determine if a novel ribonuclease (scdd-1), identified from our genetic screen, mediates the impact of U/T level on glp-1 expression; (3) investigate the potential regulation of pyrimidine metabolic pathways by U/T levels scdd-1; and (4) investigate the mechanism of scdd-1 function. By connecting nucleotide availability to developmental programs and metabolism, the results from these studies will likely present an important conceptual advance in the fields of nucleotide metabolism, development and nutritional science. Such findings may also provoke others to evaluate the impact of nucleotide quality in food or nutritional supplements on human health, especially for those with genetic risks for certain metabolic diseases.